Adrenal Causes of
Hypertension
Myron H. Weinberger
T
he adrenal gland is involved in the production of a variety of
steroid hormones and catecholamines that influence blood
pressure. Thus, it is not surprising that several adrenal disorders
may result in hypertension. Many of these disorders are potentially
curable or responsive to specific therapies. Therefore, identifying
adrenal disorders is an important consideration when elevated blood
pressure occurs suddenly or in a young person, is severe or difficult to
treat, or is associated with manifestations suggestive of a secondary
form of hypertension. Because these occurrences are relatively rare, it
is necessary to have a high index of suspicion and understand the
pathophysiology on which the diagnosis and treatment of these problems
is based.
Three general forms of hypertension that result from excessive production of mineralocorticoids, glucocorticoids, or catecholamines are reviewed
in the context of their normal production, metabolism, and feedback
systems. The organization of this chapter provides the background for
understanding the normal physiology and pathophysiologic changes
on which effective screening and diagnosis of adrenal abnormalities are
based. Therapeutic options also are briefly considered. Primary aldosteronism, Cushing’s syndrome, and pheochromocytoma are discussed.
CHAPTER
4
4.2
Hypertension and the Kidney
Adrenal Hypertension
PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION
Disorder
Cause
Pathophysiology
Pressure mechanism
Primary aldosteronism
Autonomous hypersecretion
of aldosterone (hypermineralocorticoidism)
Extracellular fluid volume
expansion, hypokalemia
(?), alkalosis
Cushing’s syndrome
Hypersecretion of cortisol
(hyperglucocorticoidism)
Pheochromocytoma
Hypersecretion of
catecholamines
Increased renal sodium and
water reabsorption,
increased urinary
excretion of potassium
and hydrogen ions
Increased activation of
mineralocorticoid
receptor (?), increased
angiotensinogen (renin
substrate) concentration
Vasoconstriction, increased
heart rate
FIGURE 4-1
The causes and pathophysiologies of the
three major forms of adrenal hypertension
and the proposed mechanisms by which
blood pressure elevation results.
Extracellular fluid volume
expansion (?), increased
angiotensin II (vasoconstriction and increased
peripheral resistance)
Increased peripheral
resistance, increased
cardiac output
Histology of the Adrenal
FIGURE 4-2
Histology of the adrenal. A cross section of the normal adrenal
before (left) and after (right) stimulation with adrenocorticotropic
hormone (ACTH) [1]. The adrenal is organized into the outer
adrenal cortex and the inner adrenal medulla. The outer adrenal
cortex is composed of the zona glomerulosa, zona fasciculata, and
zona reticularis. The zona glomerulosa is responsible for production of aldosterone and other mineralocorticoids and is chiefly
under the control of angiotensin II (see Figs. 4-3 and 4-5). The
zona fasciculata and zona reticularis are influenced primarily by
ACTH and produce glucocorticoids and some androgens (see Figs.
4-3 and 4-19). The adrenal medulla produces catecholamines and
is the major source of epinephrine (in addition to the organ of
Zuckerkandl located at the aortic bifurcation) (see Fig. 4-25.)
Capsule
Zona
glomerulosa
Zona
fasciculata
Zona
reticularis
Medulla
Normal human
suprarenal gland
Human suprarenal
gland after
administration
of crude ACTH
Adrenal Causes of Hypertension
4.3
Adrenal Steroid Biosynthesis
17α−Hydroxylase
CH3
C=O
HO
Pregnenolone
CH3
O
C=O
OH
HO
17-Hydroxypregnenolone
HO
Dehydroepiandrosterone
3 β-OH-Dehydrogenase: ∆5 ∆4 Isomerase
O
CH3
CH3
C=O
C=O
–OH
O
17-Hydroxypregnenolone
Pregnenolone
21-Hydroxylase
OH2OH
CH2OH
C=O
C=O
OH
O
11-Deoxycorticosterone
O
11-Deoxycortisol
11β-Hydroxylase
CH2OH
HO
O
HO
O
Corticosterone
18-Hydroxylase
18-OH-Dehrydrogenase
CH2OH
HO
O
CH2OH
C=O
OHC C=O
Aldosterone
Cortisol
}
Zona
glomerulosa
only
C=O
OH
O
O
∆4 Androstene 3,17-dione
FIGURE 4-3
Adrenal steroid biosynthesis. The sequence of
adrenal steroid biosynthesis beginning with
cholesterol is shown as are the enzymes
responsible for production of specific steroids
[2]. Note that aldosterone production normally occurs only in the zona glomerulosa
(see Fig. 4-2). (From DeGroot and coworkers
[2]; with permission.)
4.4
Hypertension and the Kidney
ACTH
PRA
Aldosterone
Cortisol
Morning
6 AM
Noon
6 PM
Morning
FIGURE 4-4
Circadian rhythmicity of steroid production and major stimulatory
factors. Aldosterone and cortisol and their respective major stimulatory
factors, plasma renin activity (PRA) and adrenocorticotropic hormone
(ACTH), demonstrate circadian rhythms. The lowest values for all of
these components are normally seen during the sleep period when the
need for active steroid production is minimal. ACTH levels increase
early before awakening, stimulating cortisol production in preparation for the physiologic changes associated with arousal. PRA increases abruptly with the assumption of the upright posture, followed by
an increase in aldosterone production and release. Both steroids
demonstrate their highest values through the morning and early afternoon. Cortisol levels parallel those of ACTH, with a marked decline
in the afternoon and evening hours. Aldosterone demonstrates a
broader peak, reflecting the postural stimulus of PRA.
Kidney
↓Perfusion pressure
Kidney
Juxtaglomerular
apparatus
1
↑Perfusion pressure
↓Sodium content
↑Sodium content
6
↑Extracellular fluid volume
Juxtaglomerular
apparatus
9
12
Renin
Renin
2
Angiotensin II
5
↑Extracellular fluid volume
8
↑Sodium reabsorption
Adrenal complex
Aldosterone
Zona glomerulosa
4
10
Angiotensin II
11
↑Sodium reabsorption
Adrenal complex
Aldosterone
Zona glomerulosa
7
13
14
A
Normal
K+
ACTH
B
Primary aldosteronism
K+
ACTH
FIGURE 4-5
Control of mineralocorticoid production. A, Control of aldosterone production under normal circumstances.
A decrease in renal perfusion pressure or tubular sodium content (1) at the level of the juxtaglomerular apparatus
and macula densa of the kidney triggers renin release (2). Renin acts on its substrate angiotensinogen to generate
angiotensin I, which is converted rapidly by angiotensin-converting enzyme to angiotensin II. Angiotensin II
then induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomerulosa
of the adrenal cortex (3) (see Fig. 4-2) to stimulate production and release of aldosterone (4). Potassium and
adrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances.
Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption of sodium (and
passively, water) in exchange for potassium and hydrogen ions excreted in the urine. This increased secretion
promotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that further
suppresses renin release, thus closing the feedback loop (servomechanism). B, Abnormalities present in primary
aldosteronism. Autonomous hypersecretion of aldosterone (7) leads to increased extracellular fluid volume
expansion and increased renal tubular sodium content. These elevated levels are a result of increased renal
sodium and water
reabsorption (8) at the
expense of increased
potassium and hydrogen
ion excretion in the
urine. The increase in
sodium and volume then
increase systemic blood
pressure and renal
perfusion pressure and
sodium content (9),
thereby suppressing
further renin release
(10) and angiotensin II
production (11). Thus,
in contrast to the normal situation depicted
in panel A, the levels of
angiotensin II are highly
suppressed and therefore
do not contribute to an
increase in systemic
blood pressure (12). In
primary aldosteronism,
ACTH (13) has a dominant modulatory role in
influencing aldosterone
production and hypokalemia, resulting from
increased urinary potassium exchange for
sodium, which has a
negative effect on aldosterone production (14).
4.5
Adrenal Causes of Hypertension
Aldosteronism
TYPES OF PRIMARY ALDOSTERONISM
Types
SCREENING TESTS FOR PRIMARY ALDOSTERONISM
Relative frequency, %
Solitary adrenal adenoma
Bilateral adrenal hyperplasia
Unilateral adrenal hyperplasia
Glucocorticoid-remediable aldosteronism
Bilateral solitary adrenal adenomas
Adrenal carcinoma
Test
Serum potassium ≤3.5 mEq/L
Plasma renin activity ≤4 ng/mL/90 min
Urinary aldosterone ≥20 µg/d
Plasma aldosterone ≥15 ng/dL
Plasma aldosterone–plasma renin
activity ratio ≥15
Plasma aldosterone–plasma renin
activity ratio ≥30
65
30
2
<1
<1
<1
FIGURE 4-6
Types of primary aldosteronism. (Data from Weinberger and
coworkers [3].)
Sensitivity, %
75
>99
70
90
99.8
96
Specificity, %
≈20
40–60
60
60
98
100
FIGURE 4-7
Screening tests for primary aldosteronism. Serum potassium levels
range from 3.5 to normal levels of patients with primary aldosteronism. Most hypertensive patients with hypokalemia have secondary
rather than primary aldosteronism. The plasma aldosterone-to-plasma renin activity (PRA) ratio (disregarding units of measure) is the
most sensitive and specific single screening test for primary aldosteronism. However, because of laboratory variability, normal ranges
must be developed for individual laboratory values. A random
peripheral blood sample can be used to obtain this ratio even while
the patient is receiving antihypertensive medications, when the
effects of the medications on PRA and aldosterone are considered.
(Data from Weinberger and coworkers [3,4].)
LOCALIZING TESTS FOR PRIMARY ALDOSTERONISM
Test
Adrenal computed tomographic scan
Adrenal isotopic scan
Adrenal venography
Adrenal magnetic resonance imaging
Adrenal venous blood sampling with
adrenocorticotropic hormone infusion
Sensitivity, %
Specificity, %
≈50
≈50
≈70
?
>92
≈60
≈65
≈80
?
>95
FIGURE 4-8
Localizing tests for primary aldosteronism. Adrenal venous blood
sampling with determination of both aldosterone and cortisol
concentrations during adrenocorticotropic hormone stimulation
provides the most accurate way to identify unilateral hyperaldosteronism. This approach minimizes artefact owing to episodic
steroid secretion and to permit correction for dilution of adrenal
venous blood with comparison of values to those in the inferior
vena cava. (see Fig. 4-12). (Data from Weinberger and coworkers [3].)
A
FIGURE 4-9
Normal and abnormal adrenal isotopic scans. A, Normal scan.
Increased bilateral uptake of I131-labeled iodo-cholesterol of normal adrenal tissue is shown above the indicated renal outlines.
(Continued on next page)
4.6
Hypertension and the Kidney
FIGURE 4-9 (Continued)
B, Intense increase in isotopic uptake by the left adrenal (as viewed
from the posterior aspect) containing an adenoma.
B
FIGURE 4-10
Adrenal venography in primary aldosteronism. A, Typical leaflike pattern of the normal right adrenal venous drainage. B, In
contrast, marked distortion of the normal
venous anatomy by a relatively large (3-cmdiameter) adenoma of the left adrenal.
Most solitary adenomas responsible for primary aldosteronism are smaller than 1 cm
in diameter and thus usually cannot be seen
using anatomic visualizing techniques.
A
B
Normal
Plasma aldosterone, ng/dL
60
Adenoma
Hyperplasia
50
40
30
20
10
0
8 AM
Supine
A
Noon
Upright
8 AM
Supine
B
8 AM
Supine
Noon
Upright
Noon
Upright
C
FIGURE 4-11
Changes in plasma aldosterone with upright posture. A–C, Depicted are individual data
for persons showing temporal and postural changes in plasma aldosterone concentration
in normal persons (panel A), and in patients with primary aldosteronism owing to a solitary
adrenal adenoma (panel B) or to bilateral adrenal hyperplasia (panel C). Blood is sampled
at 8 AM, while the patient is recumbent, and again at noon after 4 hours of ambulation.
In normal persons the increase in plasma
renin activity associated with upright posture
results in a marked increase in plasma aldosterone at noon compared with that at 8 AM
(see Fig. 4-4). In adenomatous primary
aldosteronism, the plasma renin activity is
markedly suppressed and does not increase
appreciably with upright posture. Moreover,
aldosterone production is modulated by
adrenocorticotropic hormone (which decreases
from high levels at 8 AM to lower values at
noon (see Fig. 4-4). Thus, these patients
typically demonstrate lower levels of aldosterone at noon than they do at 8 AM. In
patients with bilateral adrenal hyperplasia,
the plasma renin activity tends to be more
responsive to upright posture and aldosterone production also is more responsive
to the renin-angiotensin system. Thus, postural increases in aldosterone usually are
seen. Exceptions to these changes occur in
both forms of primary aldosteronism, however, making the postural test less sensitive
and specific [3].
4.7
AC
TH
TH
AC
TH
AC
AC
TH
Adrenal Causes of Hypertension
A
C
A
C
A
C
A
C
A
C
A
Bilateral aldosteronism
FIGURE 4-12
Adrenal venous blood sampling during infusion of adrenocorticotropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic
representation of the findings in primary aldosteronism owing to
bilateral adrenal hyperplasia is shown on the left. When blood is
sampled from both adrenal veins and the inferior vena cava during
ACTH infusion, the aldosterone-to-cortisol ratio is similar in both
adrenal effluents and higher than that in the inferior vena cava. In
such cases, medical therapy (potassium-sparing diuretic combinations
such as hydrochlorothiazide plus triamterene, amiloride, or spirolactone and calcium channel entry blockers) usually is effective. B,
Unilateral aldosteronism. On the right is depicted the findings in a
patient with a unilateral right adrenal lesion. This lesion can be
diagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal
A
C
B
Unilateral aldosteronism
venous blood compared with that of the left adrenal and the inferior
vena cava. Even if the venous effluent cannot be accurately sampled
from one side (as judged by the levels of cortisol during ACTH
infusion), when the contralateral adrenal venous effluent has an
aldosterone-to-cortisol ratio lower than that in the inferior vena
cava, it can be inferred that the unsampled side is the source of
excessive aldosterone production (unless there is an ectopic source).
In such cases, surgical removal of the solitary adrenal lesion usually
results in normalization of blood pressure and the attendant metabolic
abnormalities. Medical therapy also is effective but often requires
high doses of Aldactone® (GD Searle & Co., Chicago) (200 to 800
mg/d), which may be intolerable for some patients because of side
effects. A—aldosterone; C—cortisol.
4.8
Hypertension and the Kidney
FIGURE 4-13 (see Color Plate)
A section of a typical adrenal adenoma in primary aldosteronism
pathology. A relatively large (2-cm-diameter) adrenal adenoma
with its lipid-rich (bright yellow) content is shown.
180
FIGURE 4-14
Glucocorticoid-remediable aldosteronism. A–C, Seen are the effects
of dexamethasone and spironolactone on blood pressure in a father
(panel A) and two sons, one aged 6 years (panel B) and the other
aged 8 years (panel C). Blood pressure levels are shown before and
after treatment with dexamethasone (left) or spironolactone (right) [5].
Note that the maximum blood pressure reduction with dexamethasone
required more than 2 weeks of treatment. Similarly, the maximum
response to spironolactone was both time- and dose-dependent.
Father
160
140
120
100
80
mg
200
100
60
A
Son 1
Blood pressure
160
Dexamethasone
Spironolactone
140
120
100
80
60
B
200
100
40
Son 2
160
140
120
100
80
60
200
100
40
C
0
1
2
3
4
Weeks
5
6
0
2
4 6
Months
8
Adrenal Causes of Hypertension
Urinary aldosterone,
µg/ 24 h
20
15
10
5
0
1
2
3
4
20
15
10
Dexamethasone
5
B
5
1.0
0
1
2
3
4
5
50
0.8
0.6
0.4
0.2
Serum potassium, mEq/L
A
Plasma renin activity, ng AI/mL- 3hr
25
25
Plasma aldosterone,
ng/100 mL
Plasma cortisol, µg/ 100 mL
Changes with dexamethasone
40
30
20
10
7
6
5
4
3
0
C
0
1
2
3
4
5
0
D
1
2
3
4
5
E
0
1
2
3
4
Weeks
FIGURE 4-15
Humoral changes in glucocorticoid-remediable aldosteronism with dexamethasone. A–E, Depicted are the changes
in plasma cortisol (panel A), urinary aldosterone (panel B), plasma renin activity (PRA) (panel C), plasma aldosterone (panel D), and serum potassium (panel E) before and after dexamethasone administration in the patients
in Figure 4-14. Note that before dexamethasone administration, serum cortisol was in the normal range and was
markedly suppressed after treatment. Urinary aldosterone was completely normal and plasma aldosterone was
Glomerulosa
Glomerulosa
AII
AII
Aldosterone
Aldosterone
ACTH
Aldosterone
ACTH
Cortisol
Chimeric
Aldos
Fasciculata
A
Fasciculata
B
Aldosterone
Cortisol
+
Aldosterone
+
18–OH cortisol
+
18–OXO cortisol
4.9
elevated in only one
patient before dexamethasone administration. The
diagnosis was made by
demonstrating that
the plasma aldosterone
concentration failed to
suppress normally after
intravenous saline infusion (2 L/4 h) [6]. After
dexamethasone administration, both plasma and
urinary aldosterone levels
decreased markedly
(except for one occasion
when it is suspected that
the patient did not comply with dexamethasone
therapy). PRA, which was
markedly suppressed
before treatment,
increased with dexamethasone. Note also
that serum potassium
levels were normal in
two of the three patients
before treatment with
dexamethasone but
increased with therapy
in all three [5]. All of
these changes reverted to
control baseline values
when dexamethasone
therapy was discontinued.
FIGURE 4-16
Normal and chimeric aldosterone synthase
in glucocorticoid-remedial aldosteronism
(GRA). A, Normal relationship between the
stimuli and site of adrenal cortical steroid
production. Aldosterone synthase normally
responds to angiotensin II (AII) in the zona
glomerulosa, resulting in aldosterone synthesis and release (see Figs. 4-2 and 4-3). B, In
GRA, a chimeric aldosterone synthase gene
results from a mutation, which stimulates
production of aldosterone and other steroids
from the zona glomerulosa under the control
of adrenocorticotropic hormone (ACTH)
(Fig. 4-17). Thus, when ACTH production is
suppressed by steroid administration, aldosterone production is reduced.
4.10
Hypertension and the Kidney
FIGURE 4-17
Mutation of the (11-OHase) chimeric aldosterone synthase gene
[8]. The unequal crossing over between aldosterone synthase and
11-hydroxylase genes resulting in the mutated gene responsible for
glucocorticoid-remedial aldosteronism is described.
11–OHase
5'
3'
5'
3'
Unequal crossing over
5'
3'
Aldosterone synthase
5'
3'
5'
3'
5'
3'
5'
3'
Chimeric gene
11–OHase
Cushing’s Syndrome
B
A
FIGURE 4-18 (see Color Plate)
Physical characteristics of Cushing’s syndrome. A, Side profile of a patient with Cushing’s
syndrome demonstrating an increased cervical fat pad (so-called buffalo hump), abdominal
obesity, and thin extremities and petechiae (on the wrist). The round (so-called moon)
facial appearance, plethora, and acne cannot be seen readily here. B, Violescent abdominal
striae in a patient with Cushing’s syndrome. Such striae also can be observed on the inner
parts of the legs in some patients.
4.11
Adrenal Causes of Hypertension
Pituitary
Pituitary
Pituitary
CRF
(–)
(–)
(–)
Cortisol
ACTH
↑ Cortisol
ACTH
↑ Cortisol
↑ ACTH
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-19
Normal pituitary-adrenal axis. Corticotropinreleasing factor (CRF) acts to stimulate the
release of adrenocorticotropic hormone
(ACTH) from the anterior pituitary. ACTH
then stimulates the adrenal zona fasciculata
and zona reticularis to synthesize and release
cortisol (see Figs. 4-2 and 4-3). The increased
levels of cortisol feed back to suppress additional release of ACTH. As shown in Figure
4-4, ACTH and cortisol have circadian
patterns.
Adrenal cortex
(zona fasciculata
zona reticularis)
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-20
Pituitary Cushing’s disease. Pituitary Cushing’s
disease results from excessive production of
adrenocorticotropic hormone (ACTH), typically owing to a benign adenoma. Excess
ACTH stimulates both adrenals to produce
excessive amounts of cortisol and results in
bilateral adrenal hyperplasia. The increased
cortisol production does not suppress ACTH
release, however, because the pituitary tumor
is unresponsive to the normal feedback suppression of increased cortisol levels. The
diagnosis usually is made by demonstration
of elevated levels of ACTH in the face of
elevated cortisol levels, particularly in the
afternoon or evening, representing loss of
the normal circadian rhythm (see Fig. 4-4).
Radiographic studies of the pituitary (computed tomographic scan and magnetic resonance imaging) will likely demonstrate the
source of increased ACTH production. When
the pituitary is the source, surgery and irradiation are therapeutic options.
FIGURE 4-21
Adrenal Cushing’s syndrome. Adrenal
Cushing’s syndrome typically is caused by
a solitary adrenal adenoma (rarely by carcinoma) producing excessive amounts of
cortisol autonomously. The increased levels
of cortisol feed back to suppress release of
adrenocorticotropic hormone (ACTH) and
corticotropin-releasing factor. The finding
of very low ACTH levels in the face of
elevated cortisol values and a loss of the
circadian pattern of cortisol confirm the
diagnosis (see Fig. 4-4). Additional anatomic
studies of the adrenal (computed tomographic
scan and magnetic resonance imaging) usually
disclose the source of excessive cortisol production. Surgical removal usually is effective.
4.12
Hypertension and the Kidney
Cushing's syndrome: ectopic etiology
SCREENING TESTS FOR CUSHING’S SYNDROME
Ectopic
Tumor
Test
Pituitary
Elevated PM serum cortisol
Elevated urinary 17-hydroxy corticosteroids
Elevated urinary free cortisol
Sensitivity, %
Specificity, %
≈75
>90
>95
≈60
≈60
>95
(–)
Cortisol
ACTH
ACTH
FIGURE 4-23
Screening tests for Cushing’s syndrome. Whereas elevated evening
plasma cortisol levels typically indicate abnormal circadian rhythm,
other factors such as stress also can cause increased levels late in
the day. Urinary levels of 17-hydroxy corticosteroids may be
increased in association with obesity. In such cases, repeat measurement after a period of dexamethasone suppression may be required
to distinguish this form of increased glucocorticoid excretion from
Cushing’s syndrome. The measurement of urinary-free cortisol is
the most sensitive and specific screening test.
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-22
Ectopic etiology of Cushing’s syndrome. Rarely, Cushing’s syndrome may be due to ectopic production of adrenocorticotropic
hormone (ACTH) from a malignant tumor, often in the lung. In
such cases, hypercortisolism is associated with increased levels of
ACTH-like peptide; however, no pituitary lesions are found.
Patients with ectopic Cushing’s syndrome often are wasted and
have other manifestations of malignancy.
FIGURE 4-24
Algorithm for differentiation of Cushing’s syndrome. The first step in the differentiation
of Cushing’s syndrome after diagnosing hypercortisolism is measurement of plasma
adrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after
the morning hours (see Fig. 4-4). In pituitary Cushing’s disease and ectopic forms
of Cushing’s syndrome, elevated values are
observed, especially in the afternoon and
evening. The next step in differentiation is
an anatomic evaluation of the pituitary.
When no abnormality is found, the next
step is a search for a malignancy, typically
in the lung. The finding of low ACTH levels points to the adrenal as the source of
excessive cortisol production, and anatomic
studies of the adrenal are indicated. CT—
computed tomography; MRI—magnetic
resonance imaging.
Adrenal Causes of Hypertension
4.13
Catecholamines
FIGURE 4-25
Synthesis, actions, and metabolism of catecholamines. Depicted
is the synthesis of catecholamines in the adrenal medulla [9].
Epinephrine is only produced in the adrenal and the organ of
Zuckerkandl at the aortic bifurcation. Norepinephrine and dopamine
can be produced and released at all other parts of the sympathetic
nervous system. The kidney is the primary site of excretion of
catecholamines and their metabolites, as noted here. The kidney
also can contribute catecholamines to the urine. The relative
contributions of norepinephrine and epinephrine to biologic
events is noted by the plus signs. BMR—basal metabolic rate;
CNS—central nervous system; NEFA—nonesterified fatty acids;
VMA—vanillylmandelic acid.
4.14
Hypertension and the Kidney
Pheochromocytoma
Blood pressure taken at
2-min intervals
5-min intervals
150
100
240
230
220
210
190
180
170
160
140
130
120
110
90
80
70
60
40
30
20
10
0
50
Blood pressure, mm Hg
200
250
Calibrate
8:30
10
2
5:00
7:45
9
10
11
PM
PM
AM
AM
AM
AM
AM
AM
12
Noon
1
PM
During the attack:
Blood pressure, 192/100 mm Hg
Pulse 108
Respirations, 24
FIGURE 4-26
Paroxysmal blood pressure pattern in pheochromocytoma.
Note the extreme variability of blood pressure in this patient
with pheochromocytoma during ambulatory blood pressure
monitoring [9]. Whereas most levels were within the normal
FIGURE 4-27 (see Color Plate)
Neurofibroma associated with pheochromocytoma. Neurofibromas
are sometimes found in patients with pheochromocytoma. These
lesions are soft, fluctuant, and nontender and can appear anywhere
on the surface of the skin. These lesions can be seen in profile in
Figure 4-28.
range, episodic increases to levels of 200/140 mm Hg were
observed. Such paroxysms can be spontaneous or associated
with activity of many sorts. (Adapted from Manger and Gifford
[9]; with permission.)
FIGURE 4-28
Café au lait lesions
in a patient with
pheochromocytoma.
These light-browncolored (coffeewith-cream-colored)
lesions, sometimes
seen in patients with
pheochromocytoma,
usually are larger
than 3 cm in the
largest dimension.
In this particular
patient, neurofibromas also are present
and can be seen in
profile.
4.15
Adrenal Causes of Hypertension
DISORDERS ASSOCIATED WITH
PHEOCHROMOCYTOMA
FIGURE 4-29
Disorders associated with pheochromocytoma. In addition to the neurofibromas and
café au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormalities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9];
with permission.)
Cholelithiasis
Renal artery stenosis
Neurofibromas
Café au lait lesions
Multiple endocrine neoplasia, types II and III
Von Hippel-Lindau syndrome
(hemangioblastoma and angioma)
Mucosal neuromas
Medullary thyroid carcinoma
COMMON SYMPTOMS
AND FINDINGS IN
PHEOCHROMOCYTOMA
Patients, %
Symptoms
Severe headache
Perspiration
Palpitations, tachycardia
Anxiety
Tremulousness
Chest, abdominal pain
Nausea, vomiting
Weakness, fatigue
Weight loss
Dyspnea
Warmth, heat intolerance
Visual disturbances
Dizziness, faintness
Constipation
Finding
Hypertension:
Sustained
Paroxysmal
Pallor
Retinopathy:
Grades I and II
Grades III and IV
Abdominal mass
Associated multiple endocrine
adenomatosis
82
67
60
45
38
38
35
26
15
15
15
12
7
7
61
24
44
40
53
9
6
FIGURE 4-30
Common symptoms
and findings in pheochromocytoma. Note
that severe hypertensive retinopathy,
indicative of intense
vasoconstriction,
frequently is
observed. (Adapted
from Ganguly
et al. [10].)
SCREENING AND DIAGNOSTIC TESTS
IN PHEOCHROMOCYTOMA
Test
Elevated 24-h urinary catecholamines,
vanillylmandelic acid, homovanillic
acid, metanephrines
Abnormal clonidine suppression test
Elevated urinary “sleep” norepinephrine
Sensitivity, %
Specificity, %
≈85
≈80
≈75
>99
≈85
>99
FIGURE 4-31
Screening and diagnostic tests in pheochromocytoma. Drugs, incomplete urine collection, and episodic secretion of catecholamines can
influence the tests based on 24-hour urine collections in a patient
with a pheochromocytoma. The clonidine suppression test is fraught
with false-negative and false-positive results that are unacceptably
high for the exclusion of this potentially fatal tumor. The “sleep”
norepinephrine test eliminates the problems of incomplete 24-hour
urine collection because the patient discards all urine before retiring;
saves all urine voided through the sleep period, including the first
specimen on arising; and notes the elapsed (sleep) time [10]. The sleep
period is typically a time of basal activity of the sympathetic nervous
system, except in patients with pheochromocytoma (see Fig. 4-32).
4.16
Hypertension and the Kidney
Sleep urinary norepinephrine excretion, µg
1000
Patient I
Patient II
Patient III
Patient IV
Patient V
Patient VI
100
FIGURE 4-32
Nocturnal (sleep) urinary norepinephrine. The values for urinary
excretion of norepinephrine are shown for normal persons and
patients with essential hypertension as mean plus or minus SD
[10]. Values for patients with pheochromocytoma are indicated by
symbols. Note that the scale is logarithmic and the highest value
for patients with normal or essential hypertension was less than 30
µg, whereas the lowest value for a patient with pheochromocytoma
was about 75 µg. Most patients with pheochromocytomas had values an order of magnitude higher than the highest value for
patients with essential hypertension.
Maximum for normal
Maximum for hypertensive
10
Hypertensive
mean + SD
Normal
mean + SD
0
LOCALIZATION OF PHEOCHROMOCYTOMA
Test
Abdominal plain radiograph
Intravenous pyelogram
Adrenal isotopic scan
(meta-iodobenzoylguanidine)
Adrenal computed tomographic scan
Sensitivity, %
Specificity, %
≈40
≈60
≈85
≈50
≈75
≈85
>95
>95
FIGURE 4-33
Localization of pheochromocytoma. Once the diagnosis of
pheochromocytoma has been made it is very important to localize
the tumor preoperatively so that the surgeon may remove it with a
minimum of physical manipulation. Computed tomographic scan
or MRI appears to be the most effective and safest techniques for
this purpose [10]. The patient should be treated with -adrenergic
blocking agents for 7 to 10 days before surgery so that the contracted
extracellular fluid volume can be expanded by vasodilation.
FIGURE 4-34
Intravenous pyelogram in pheochromocytoma. Note the
displacement of the
left kidney (right) by
a suprarenal mass.
Adrenal Causes of Hypertension
A
B
C
D
FIGURE 4-35
A–D, Computed tomographic scans in four patients with pheochromocytoma [10]. The black arrows identify the adrenal tumor in
A
FIGURE 4-36 (see Color Plates)
A and B, Pathologic appearance of pheochromocytoma before
(panel A) and after (panel B) sectioning. This 3.5-cm-diameter
4.17
these four patients. Three patients have left adrenal tumors, and in
one patient (panel B) the tumor is on the right adrenal.
B
tumor had gross areas of hemorrhage noted by the dark areas
visible in the photographs.
4.18
Hypertension and the Kidney
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